Management of End-Stage Sarcoidosis: Pulmonary ...

[Pages:46]ERJ Express. Published on January 12, 2012 as doi: 10.1183/09031936.00175511 Management of End-Stage Sarcoidosis: Pulmonary Hypertension and Lung Transplantation Oksana A Shlobin, MD Steven D Nathan, MD Advanced Lung Disease and Transplant Program Inova Fairfax Hospital Falls Church, VA

Copyright 2012 by the European Respiratory Society.

Outline

1) Introduction

2) Pulmonary hypertension a. Overview b. Pathophysiology of PH in Sarcoidosis c. Impact and Outcomes of PH in Sarcoidosis d. Clinical Presentation and Diagnostic Testing e. Management of PH in Sarcoidosis i. The Endothelin Pathway ii. Nitric Oxide and Phosphodiesterase Inhibitors iii. The Prostacyclin Pathway iv. Conclusion

3) The Role of Lung Transplantation a. Overview b. Sarcoidosis Specific Issues: Implications for Transplantation i. Sarcoidosis as a Multisystem Disease ii. Parenchymal Complications 1. Cavities and Mycetomas 2. Bronchiectasis c. Transplant Operative Considerations d. Post Transplant Outcomes e. Conclusion

1) Introduction

Sarcoidosis is not only a multisystem, but also a multinational disease that is prevalent throughout the world including in Europe, the United States and Japan (1, 2). In Europe, especially in the Scandinavian countries and Ireland, it affects the Caucasian population, while in the United States it tends to occur in African-Americans more commonly. It has a reported incidence in females of 21.6 and in males 15.3 cases per 100,000 population per year (2).

Lung involvement in sarcoidosis is seemingly invariable with up to 95% of patients manifesting some form of pulmonary disease during the course of their lifetime (1). On the other hand, the natural history of sarcoidosis in the lung is quite variable and spans the spectrum from spontaneous resolution to advanced fibrocystic disease. Fortunately, in most cases, there is more of a propensity for the former and more benign clinical course. However, in about 5% of cases permanent severe pulmonary dysfunction occurs which accounts for most the morbidity and mortality seen with the disease (Figure 1) (1). Indeed, respiratory failure is the most common cause of death from sarcoidosis in the United States and Europe as opposed to Japan where cardiac sarcoidosis is the major cause of mortality (3). Advanced sarcoidosis will be the subject of this review with a special focus on pulmonary hypertension and lung transplantation as a last resort treatment option for select patients with end-stage disease.

2) Pulmonary Hypertension a. Overview Sarcoidosis is characterized pathologically by non-caseating granulomas and it is

the sequela of these that determine the clinical manifestations of the disease. Patients who progress to develop stage IV fibrocystic disease commonly manifest physiologically with varying degrees of restrictive and obstructive disease and a decreased diffusion capacity (1). Pulmonary hypertension (PH) is an increasingly recognized complication of sarcoidosis with a reported prevalence between 1 and 28% of all patients at rest and up to 43% with exercise (4, 5, 6). PH most commonly occurs in association with advanced stage IV disease, but can also occur in the context of relatively normal lung function and preserved parenchymal architecture. Patients with recalcitrant dyspnea and normal left ventricular function have a higher reported PH prevalence of approximately 53% (7). Sarcoidosis patients who are listed for lung transplantation have an even higher rate of ~74% (8). In our own clinic, we have found a similar prevalence of PH (~75%) based on right heart catheterization of 104 transplant and non-transplant candidates with advanced sarcoidosis evaluated over a 14 year period (Figure 2).

b. Pathophysiology of PH in Sarcoidosis The most recent World Health Organization (WHO) conference (Dana Point, California 2008), categorized PH into five groups. Group I or Pulmonary Arterial Hypertension (PAH) includes the prototypical disease of idiopathic pulmonary arterial hypertension and other forms of associated PAH, while group II is PH related to left sided heart disease, group III is seen in association with lung disease, group IV is due to chronic thromboembolic disease and group V is comprised of miscellaneous conditions. Sarcoidosis is categorized within the last group since the pathogenesis of associated PH is complex and multifactorial with characteristics and similarities to all four former groups (Figure 3) (9, 10). The majority of sarcoidosis patients with PH has stage IV disease and associated impaired pulmonary function tests (PFTs) (Figure 2) (11). PH is therefore usually attributed to the destruction of the capillary bed by the fibrotic process and/or regional hypoxemic vasoconstriction. However, the severity of PH does not always correlate with

the degree of parenchymal lung disease and blood gas abnormalities, suggesting that other mechanisms may be playing a role (Figure 3) (4, 8, 11). These other contributors may be directly related to the pulmonary vasculature or extrapulmonary, either within the mediastinum or in the form of an associated co-morbidity.

Granulomatous involvement of the pulmonary vessels is common in sarcoidosisassociated PH, and has been described in 69-100% of patients with PH (12). The granulomatous inflammation tends to involve the lung in a lymphatic distribution, thus neighboring the granulomas adjacent to the pulmonary arteries and veins in the bronchovascular bundles and interlobular septae. The granulomas may be found in all layers of the vessel wall, but other pathologic findings are commonly seen, including inflammation, necrosis, destruction of the musculoelastic media of the small and medium-sized vessels, endothelial proliferation and disruption of the basal lamina. As a result, an occlusive vasculopathy may develop, especially in the small arterioles and venules (12, 13). When the granulomatous infiltration involves the pulmonary veins preferentially, this may result in a clinical picture that mimics pulmonary veno-occlusive disease (PVOD) (14, 15, 16). In addition, an intrinsic venopathy may result in a PVOD like picture (11). In-situ thrombosis (thrombotic angiopathy) is another intravascular mechanism which has been described (13). More proximally, mediastinal or hilar adenopathy and any accompanying fibrosis can result in mechanical extrinsic compression of the large pulmonary arteries and an increased pulmonary vascular resistance (Figures 1, 4) (11, 17, 18, 19).

The geographical distribution of the non-caseating granulomas and fibrosis differentiates the PH related to sarcoidosis from WHO group I PAH, which tends to involve the pulmonary vasculature in a more homogenous fashion. Typically the architectural distortion that results from fibrocavitary disease favors a more central and upper lobe distribution. Parenchymal remodeling may also result in vessel tortuosity, turbulent flow and shear stresses which may perpetuate the development and progression of PH (20). The heterogenous distribution of disease might contribute to the apparent dissociation between the degree of restrictive physiology, a surrogate for the parenchymal disease burden, and the prevalence and severity of PH. The central predilection specifically may involve the proximal lobar vessels with a greater propensity for the

subsequent development of PH. Fibrosis in proximity to the pulmonary arterial circulation may also adversely affect the vascular capacitance, a surrogate of vessel stiffness. A low vascular capacitance has been demonstrated to portend a worse prognosis in patients with PAH (21). If the same holds true for the PH of sarcoidosis, this might help explain the significant mortality implications of even mild elevations in PA pressures.

There are a number of cytokines that have been found to be up-regulated in sarcoidosis that could perpetuate the development of PH. One such example is endothelin-1 (ET-1), which has been implicated in the pathogenesis of both idiopathic PAH and various interstitial lung diseases (22, 23, 24). ET-1 is produced primarily by endothelial cells, smooth muscle and airway epithelial cells, with production induced by hypoxia, shear stress and various growth factors and cytokines (24). It is a potent vasoconstrictor which is also thought to have long term vascular remodeling properties (24). Tumor necrosis factor (TNF) alpha, which is thought to play a central role in the pathogenesis of sarcoidosis, has also recently been implicated in the inflammatory pathway of PAH (25, 26). Conceptually therefore, the up regulation of these, and perhaps other cytokines, may contribute to the development of PH. The prospect of cytokine "cross-talk" may therefore provide an additional explanation for the disproportionate PH that is seen in the context of well-preserved lung volumes.

There also may be increased pulmonary vasoreactivity in sarcoidosis, as suggested by the favorable acute response to vasodilators, including nitric oxide (NO) and prostacyclin. The mechanism for this is not clear, but may be partially explained by endothelial damage from sarcoidosis granulomas, with a subsequent decrease in synthesis and release of NO and prostaglandins. This may have long-term sequela with chronic, pulmonary vasoconstriction and associated remodeling (27, 28).

In some cases, extra-pulmonary manifestations of sarcoidosis may also contribute to the development of PH. Not infrequently, direct myocardial involvement by granulomas and myocardial fibrosis may lead to left ventricular systolic and diastolic dysfunction (29). In one study, 30% of sarcoidosis patients with evidence of PH demonstrated elevated pulmonary capillary wedge pressures (PCWP). This underscores the need to rule out left-sided heart disease in the comprehensive evaluation of PH related

to sarcoidosis (30). As with all forms of PH, right heart catheterization is therefore mandatory in establishing the diagnosis.

Hepatic granulomatous infiltration and subsequent cirrhosis may be seen as a complication of the disease, and therefore porto-pulmonary hypertension should be considered in patients with stigmata of liver dysfunction (31). Other common comorbidities, which are not necessarily sarcoidosis-specific, including obstructive sleep apnea (OSA), should not be overlooked if patients are thus predisposed. Indeed, the prevalence of OSA in sarcoidosis has been reported to be 17%, which is much higher than what might be expected in a healthy patient population (32). Finally, while chronic thromboembolic disease should be considered as a potential cause of or contributor to PH, acute pulmonary embolism might also warrant exclusion in the context of new acute or subacute shortness of breaths and/or signs of increasing right-sided heart failure (33, 34).

c. Impact and Outcomes of PH in Sarcoidosis The presence of PH has been shown to be associated with greater supplemental oxygen requirements, reduced functional capacity and greater caregiver dependency (35). The mortality implications of any PH, both precapillary and venous, in the context of sarcoidosis are also profound with a >10-fold increase in mortality and an estimated 5 year survival of only 59% (11, 30). Sarcoidosis PH patients are more likely to be listed for lung transplantation and not surprisingly, also have a greater likelihood of succumbing while on the wait list (8, 36). One of the issues in sarcoidosis, as with all forms of parenchymal lung disease associated PH, is whether patients are succumbing because of PH or in the presence of PH. With regards to the latter scenario, it might be that PH is a surrogate for another disease-related process that is driving mortality. In one study which demonstrated that PH was associated with sarcoidosis mortality, the only hemodynamic factor that remained predictive of mortality after multivariable analysis was the right atrial pressure (RAP) (36). Moreover, this study also demonstrated hemodynamic progression of PH in the patient cohort. This evidence of right-sided heart

failure infers that patients with sarcoidosis-related PH are indeed dying from their PH, rather than the PH being an epiphenomenon.

d. Clinical Presentation and Diagnostic Testing The diagnosis of PH in sarcoidosis can be difficult as the most common symptom is dyspnea on exertion which is frequently attributed to the underlying parenchymal lung disease (37). One study reported no difference in the presenting symptoms of sarcoidosis patients with and without concomitant PH (4). PH should be suspected in any patient with signs and symptoms of right-sided congestive heart failure, especially lower extremity edema. However, the clinical signs of right-sided heart failure have a low sensitivity, manifesting in as few as 21% of patients with PH (4). Therefore a high index of suspicion needs to be maintained, especially in patients with symptoms that appear to be out of proportion to the degree of parenchymal lung disease, or who have more subtle signs of PH including a loud or palpable P2 heart sound. Although PH is more common in patients with advanced fibrosis, there are no specific radiographic findings that predict the presence or absence of PH (5, 11). Chest roentonography frequently shows evidence of hilar adenopathy, however hilar fullness may also be due to pulmonary artery enlargement. In this regard, computed tomography (CT) chest scans can be very helpful in providing the structural detail necessary to discern these. The presence of large PA segments on CT scanning should raise the suspicion for underlying PH, although the predictive accuracy of this finding does require further study. There are additional CT findings that should raise the suspicion for PH including evidence of extrinsic compression of large pulmonary arteries by lymphadenopathy or fibrosis (Figure 4). Blood tests that have been shown to correlate with the presence or severity of PAH include brain natriuretic peptide (BNP) and N-terminal fragment?proBNP (NTproBNP) levels. There is data to suggest that an elevated BNP is a marker of a poor prognosis in patients with chronic lung diseases (38). In one study of patients with interstitial lung disease, an elevated BNP was the strongest predictor of overall mortality, independent of the severity of the underlying fibrosis (39). However, the BNP might be a global biomarker of cardiac dysfunction, rather than being specific for PH. Indeed, in a

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